Acute renal failure has a high morbidity and mortality. We have finished developing a set of new model of sepsis-induced ARF that employ cecal ligation puncture in elderly mice treated with fluids and antibiotics. We get increases in creatinine and modest changes in renal histology - similar to human ARF - along with clear evidence of injury in other organs (lung, liver, muscle, etc). These models are very exciting because the mice are treated with fluids and antibiotics, as occurs to humans with sepsis. We are now studying the pathophysiology of injury, screening drugs, and studying their mechanisms of action. We have used the model to screen for drugs that inhibit renal and multiorgan damage. We have found three drugs (Ethyl pyurvate, Pirfenidone, RDT2, and RDT3) that inhibit renal injury, even when first started 8-12 hours after induction of sepsis. We found that blocking TNFa or TRL2 receptors has no effect on ARF. However, we can block renal injury, without altering sepsis using a knock-out system. We have also performed microarray experiments to search for new drug targets and biomarkers, and additional studies that investigate the mechanism of disease.